SRC-3 Promotes Osteogenic Differentiation by Regulating the Wnt/β-catenin Pathway to Alleviate Osteoporosis

Abstract

Background: The disorders of bone resorption and bone formation processes may contribute to the progression of osteoporosis (OP). Moreover, the human bone marrow mesenchymal stem cells (hBM-MSCs) are precursor cells of osteoblasts. Exploring the differentiation mechanism of hBM-MSCs holds immense significance for the prevention and treatment of OP. Furthermore, the steroid receptor coactivator-3 (SRC-3), an important co-activator of estrogen receptor and estrogen-related receptor α, may serve as an important regulator of bone metabolism. However, there are limited studies available on the role as well as the molecular mechanism of SRC-3 in postmenopausal OP (PMOP). Therefore, this study investigated the role of SRC-3 in hBM-MSCs osteogenic differentiation (OD) and delved into its underlying regulatory mechanism. Methods: A total of 60 study subjects, including 30 PMOP patients (OP group) and 30 healthy menopausal women (non-OP (NOP) group) were recruited in this study. Serum SRC-3 levels were assessed using enzyme-linked immunosorbent assay (ELISA). Furthermore, 10 nmol/L of dexamethasone, 10 mmol/L of β-glycerolphosphate, and 50 μg/mL of ascorbic acid were added to the culture medium to induce OD in hBM-MSCs. The expression level of SRC-3 was evaluated employing real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis following OD induction. The impact of SRC-3 on the OD and mineralization of hBM-MSCs was assessed by analyzing alkaline phosphatase (ALP) activity and alizarin red staining (ARS) procedure. Furthermore, changes in the expression levels of OD indicators and Wnt3a/β-catenin were determined by RT-qPCR and Western blot analysis. Results: The expression level of SRC-3 was significantly reduced in the serum of PMOP patients (p < 0.0001). However, OD was successfully induced (p < 0.01, p < 0.001, p < 0.0001) and the expression of SRC-3 was upregulated by SRC-3 overexpression vector (p < 0.01, p < 0.001). Furthermore, SRC-3 overexpression promoted OD of hBM-MSCs (p < 0.01, p < 0.001, p < 0.0001) as well as up-regulated the expression of Wnt3a and β-catenin (p < 0.05, p < 0.01, p < 0.001, p < 0.0001). Moreover, the inhibition of Wnt3a or β-catenin was found to reverse the promotion of SRC-3 on OD of hBM-MSCs (p < 0.05, p < 0.001, p < 0.0001). Conclusion: In summary, we observed significantly reduced serum SRC-3 level in PMOP patients. Furthermore, SRC-3 overexpression promoted OD and mineralization of hBM-MSCs through the activation of the Wnt/β-catenin signaling pathway, thereby ameliorating OP.